Block B - cholesterol and statins

Question 1

major factors for cornary risk ?

Answer 1

age, male gender, smoking and high blood pressure (hypertension) as well as Elevated cholesterol of LDL-C, low HDL-c and diabetes and family history (genetics)

Question 2

minor factors ?

Answer 2

Minor factors include sedentary lifestyle, obesity, dietary saturated fats.

Question 3

what are C reactive proteins a marker for ?

Answer 3

inflammation

Question 4

primary prevention ?

Answer 4

Primary prevention has the aim of reducing formation and rate of progression in coronary and peripheral atherosclerosis from childhood to old age. The prevention of coronary events and strokes in apparently healthy persons at risk, particularly middle-aged and elderly. Furthermore, the prevention of heart attacks, strokes in persons with established atherosclerosis.

Question 5

describe the liver ?

Answer 5

The liver is complex organ, located in the upper right corner of the abdomen in the thoracic cavity. It consists of two main lobes divided into right and left by the hepatic vein .The liver received approximately 15 ml of blood per minute from two major vessels: The hepatic artery supplies 25% of the total blood flow and provides most of the oxygen requirement. The portal vein drains most of the gastrointestinal tract (GI). It supplies 75% of the blood flow and transports the most recently absorbed material from the intestines to the liver. Drugs undergo first pass metabolism here , which can influence the amount of drug available.

Question 6

what does the liver produce ?

Answer 6

Liver produces bio salts which act as an emulsion, these are stored in the gallbladder. Then following stimulation from the pancreas, it feeds bile into the duodenum to reduce the pH environment from the stomach. A key component of bile is cholesterol.

Question 7

function of he liver ?

Answer 7

The liver stores glycogen, vitamins and iron.It contains an extensive reticuloendothelial system for the synthesis and breakdown of blood cells. The blood cells are then resynthesized with the heme (iron component) stored in the liver. Liver cells metabolize, detoxify and excrete through bile which moves through the small intestine, both endogenous and exogenous compounds by first pass metabolism. This is important in metabolism and execration of drugs and toxins.

Question 8

ideal cholesterol level ?

Answer 8

target for cholesterol is 4-5 mmol/L and American expression is 200mg/dl-1.

Question 9

target for HDL ?

Answer 9

The target for HDL ( good one) is around 1mmol/L

Question 10

target for LDL ?

Answer 10

LDL ( bad one) is less than 2-3 mmol/L

Question 11

target for triglycerides ?

Answer 11

Triglycerides are smaller than the LDL particles and a target for them is less than 1.7mmol/L.

Question 12

ratio of HDL:LDL ?

Answer 12

The ratio of HDL:LDL is ideally less than 4.5mmol/L.

Question 13

patient with high cholesterol , what will the ratio be ?

Answer 13

have a higher ratio of LDL compared to HDL. This means there is a lipid profile in the blood that would favour the development of atherosclerotic plaques. The oxidation of LDL and the immune cells such as macrophages and monocytes lead to the generation of the foam cell.

Question 14

description of cholesterol ?

Answer 14

Cholesterol is a waxy , fat like substance that is a sterol , steroid alcohol. It is found in all cells of the body as it is part of the lipid bilayer. 75% of the cholesterol is synthesised in the liver due to resynthesis occurring and the other 25% comes from our diet , denovo.

Question 15

cholesterol synthesis ?

Answer 15

cholesterol synthesis occurs primarily in the liver, cytoplasm and the Endoplasmic Reticulum in endothelial cells which involves over 30 enzymes. The HMG-CoA reductase reaction is the rate limiting step as it is at the start of the reaction. This stage is highly regulated and a target of pharmacological intervention. Statins target this step in cholesterol synthesis by blocking the enzyme HMG-coA reductase which in turn blocks the production of mevalonic acid and the further steps in cholesterol synthesis.

Question 16

what is cholesterol in ?

Answer 16

Cholesterol is in the sex hormones such as testosterone and also by hormones released by the adrenal gland

Question 17

why is synthesis of cholesterol important ?

Answer 17

It is also used in the production of bile acids which are used for neutralization. Vitamin D synthesis requires cholesterol to be present.

Question 18

chylomicrons ?

Answer 18

Chylomicrons are small fat globules composed of protein and fat. There are different types as follows: Very low density lipoproteins (VLDL) , Intermediate-density lipoproteins (IDL) , Low density lipoproteins (LDL) and High density lipoproteins (HDL).

Question 19

athersclerosis ?

Answer 19

Atherosclerosis is the formation of fatty plaques in the blood vessels and they can lead to heart attacks , strokes , angina and an increased risk of coronary heart disease. This is due to a narrowing of the artery and this causes an abnormal blood flow and oxygen delivery. A key factor here is the LDL molecules. The oxidation of LDL and the immune cells such as macrophages and monocytes lead to the generation of the foam cell. This foam cell undergoes apoptosis and forms a core for the ealry stage of a plawue.

Question 20

Drug therapy for hyperlipidemia include bile sequestriants , what are these ?

Answer 20

sequester the bile which is excreted , this causes more of the available cholesterol to be used in producing bile and as a result the concentration of cholesterol decreases.

Question 21

Niacin ?

Answer 21

B vitamins , important in synthesis , quite small not normally a large factor for reducing. Used for people which have liver diseases as an add on.

Question 22

fibric acid derivitives ?

Answer 22

good for binding fat and cholesterol which is in our diet , so it is not absorbed by the GI tract.

Question 23

why is the medditeranian diet good for ?

Answer 23

The Mediterranean diet is rich in plant oil , it is beneficial for having a good balance of lipids in the blood, as a result the ratio of LDL is lower , HDL is high and cholesterol is decreased.

Question 24

Ezetimibe’s ?

Answer 24

Ezetimibe’s will reduce the fat being taken up from the gut

Question 25

effect of statins ?

Answer 25

Statins have the greatest effect at reducing the LDL and as a result cholesterol , an increase in the HDL a about 5 to 15%

Question 26

mechanism of action of statins ?

Answer 26

Statins inhibit an early and rate limiting step in cholesterol biosynthesis, the HMG-CoA reductase.Inhibiting hepatic cholesterol synthesis results in increased expression of the LDL receptor gene, this decreases free cholesterol causes membrane-bound SREBPs to be cleaved and translocated to the nucleus to bind the sterol responsive element of the LDL receptor gene. This enhances transcription and increases the synthesis of LDL receptors

, It also reduces the degradation of LDL receptors.

Question 27

statins and HMG-CoA reductase ?

Answer 27

The use of statins blocks HMG-CoA reductase and the production of mevalonate. The blocking of mevalonate will prevent the synthesis of biological molecules such as Farnesyl pyrophosphate producing Farnesylated proteins. Also, the production of E,E,E-Geranylgeranyl pyrophosphate, which play an important role in disease progression such as cancer.

Question 28

how does blocking mevalonate effct ?

Answer 28

By statins blocking the production of mevalonate, this has a knock-on effect on the available LDL and HDL in the blood. By blocking mevalonate, this has a knock-on effect on the geranyl Geranyl pyrophosphate which are monomeric G proteins such as Rho and Rac , Rho kinase has a negative effect on the endothelial nitric oxide synthase ( eNOS). If this pathway was not blocked by the statin, then there is increased Rho which will negate the beneficial effect of eNOS. It will also increase the monomeric G protein Rac which has an effect on the NAD(P)H- oxidase system that produces several reactive oxygen species such as hydrogen peroxide and super oxide. These are related to a number of disease conditions. This is an additional benefit of statins, less inhibition of Rho which in turn increases the amount of eNOS available which is good. Stains will also decrease the NADP-oxidase levels present

Question 29

HMG-CoA reductase inhibitors ?

Answer 29

The additional secondary effects of statins are available above and these are called pleotropic effects.

Factors that lead to atherosclerosis and cardiovascular disease include platelet activation, thrombotic effects, plaque stability, vascular inflammation, Smooth Muscle Cell hypertrophy, endothelial dysfunction, Smooth Muscle Cell proliferation and vasoconstriction. Above all the main factor for developing atherosclerosis is hypertension. People that take statins will have a lower production of thromboxane which lowers platelet activation, it will also decrease macrophage growth and production, statins will decrease the C reactive protein level in a patient which in turn will reduce the levels of inflammation. Statins also have an effect in ET-1 and the angiotensin 1 receptor which are involved in vasoconstriction.

Question 30

side effects of statins ?

Answer 30

however rhabdomyolysis is a common side effect of statins use in 1-2 people of 100 group which is muscle wastage and weakness as well as type 2 diabetes.

Question 31

statins effect on Triglycerides ?

Answer 31

Statins decrease triglycerides in hypertriglyceridemic by 35-45%. Increase HDL-C in Normal patients: 5-10% and patients with low levels the patients: 15-20%. There is a decrease LDL-C by about 20-55%. Non-lipid lowering effects include endothelial function (Enhances production of nitric oxide), this is an anti-inflammatory effect measured by C reactive proteins and reduce venous thromboembolic events by 43% as statins are anti coagulants.

Question 32

adverse effects >

Answer 32

Adverse Effects include hepatotoxicity, which is an elevated hepatic transaminase values, by the liver enzyme concentration and kidney function test. There is one case of liver failure per million person-years of use. Myopathy has one death per million prescriptions caused by rhabdomyolysis, creatine kinase enzyme is a test used to confirm this rhabdomyolysis

Question 33

when is atorvostatin used ?

Answer 33

Atorvastatin is used for secondary prevention and it is a higher concentration of drug that is used. The lower the cholesterol LDL level is the , the lower the risk of having an event rate (%).

Question 34

ROSUVASTAIN ?

Answer 34

Rosuvastatin can result in atherosclerotic plaque regression , an ultrasound is used to check the lumen size.